Amino pyrimidine anticancer compounds
Compounds of Formula 1, as shown below and defined herein: and pharmaceutically acceptable salts, synthesis, intermediates, formulations, and methods of disease treatment therewith, including cancers mediated at least in part by FAK.
1. A compound of Formula 1:
wherein:
R1 is halogen, —CF 3 , or —CCH;
at least one of Q 2 to Q 4 is >C—X 1 —R2;
Q 1 and the remaining Q 2 to Q 4 are independently >CH, >CF, >N, or >N-oxide;
X 1 and X 2 are independently —(CR 7 R 8 ) 0-2 —;
each R 7 and R 8 is independently halogen, C 0-3 aliphatic, or —OC 0-3 aliphatic, either of which is optionally halogen substituted, except that in the case of X 2 , R 7 and R 8 are not halogen or —OC 0-3 aliphatic;
R6 is halogen, —OC 0-3 aliphatic, or C 0-3 aliphatic, either optionally substituted by one or more halogen or by —OCF 3 ;
R2 is —P(O)R 9 R 10 ;
R 9 and R 10 are independently C 0-3 aliphatic, either of which can be taken together at any of their atoms to form a ring, wherein any of the foregoing can be further substituted by one or more halogen, C 0-6 aliphatic, or 3-6 cyclic;
R is
one of Q 6 , Q 7 , or A is >CR4;
Q 5 and the remaining Q 6 to Q 7 and A are independently >CH, >CF, >N, or >N-oxide;
R3 is C 0-6 aliphatic, —S(O) 2 R 11 , —S(O) 2 NR 11 R 12 , —C(O)NR 11 R 12 , —C(O)OR 11 ; —NR 11 S(O) 2 R 12 , or —NR 11 R 12 ;
R 11 and R 12 are independently C 0-6 aliphatic, which can be taken together at any of their atoms to form a ring containing 1-3 heteroatoms;
or alternatively R3 and A define any optionally substituted 5-6 cyclic containing one or more heteroatoms;
R4 is 4-6 cyclic, —OC 0-6 aliphatic, or C 0-6 aliphatic, each optionally substituted, or halogen;
or a pharmaceutically acceptable salt thereof.
2. The compound or salt of claim 1 , wherein:
Q 3 is >C—CH 2 —R 2 ; and R 9 and R 10 are independently C 0-3 alkoxy.
3. The compound or salt of claim 2 , wherein R4 is optionally substituted cyclohexyl.
4. The compound or salt of claim 1 , having the Formula 1a:
wherein:
X 1 and X 2 are independently —(CR 7 R 8 ) 0-1 —;
R is
A is CH or N;
R1 is halogen, —CF 3 , or —CCH;
R2 is —P(O)R 9 R 10 ;
R3 is —S(O) 2 R 11 , —S(O) 2 NR 11 R 12 , —C(O)NR 11 R 12 , —C(O)OR 11 ; —NR 11 S(O) 2 R 12 , or —NR 11 R 12 ;
R4 is -x-y-z, wherein:
x is 4-6 cyclic; y is absent or 4-6 heterocyclic; and z is absent or C 1-3 alkyl optionally substituted by 1-2 hydroxy or C 1-6 alkoxy groups, or z is hydroxy or —C(O)O—C 0-3 alkyl; or
-x-y-z is C 0-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, or C 0-6 alkyl, each optionally substituted by 1-2 hydroxy groups;
R5 is C 0-2 alkyl optionally substituted by 1-3 independent hydroxy or halogen groups;
R6 is halo, —C 0-3 alkoxy, —C 0-3 alkyl optionally substituted by halo, or —OCF 3 ;
each R 7 and R 9 is independently H or —CH 3 ;
R 9 and R 10 are independently hydroxy, C 1-6 alkoxy, or C 0-6 alkyl, any of which can be taken together at any of their atoms to form a ring, or aryl, —O-aryl, or 4-6 heterocyclic, wherein any of the foregoing can be further substituted by 3-6 cyclic;
R 11 and R 12 are independently C 0-6 alkyl, which can be taken together at any of their atoms to form a ring containing 1-3 heteroatoms; R 11 or R 12 can independently be taken at any of their atoms with the ring to which R3 is attached to form a ring.
5. The compound or salt of claim 4 , wherein:
X 1 and X 2 are independently a bond or methylene and X 1 is meta or para to the position of nitrogen attachment;
R is
A is CH or N;
R1 is Cl, Br, or —CF 3 ;
R3 is —N(CH 3 )S(O) 2 CH 3 or —C(O)NHCH 3 ; and
R6 is H or methoxy.
6. The compound or salt of claim 5 , wherein R 9 and R 10 are independently C 0-4 alkoxy.
7. The compound or salt of claim 6 , wherein X 1 is a methylene group positioned meta to R6.
8. The compound or salt of claim 7 , wherein:
A is CH;
X 2 is a bond;
R1 is —CF 3 ; and
R3 is —C(O)NHCH 3 .
9. The compound or salt of claim 1 , having the formula:
wherein R6 is H or methoxy; and
R9 and R10 are independently C 0-3 alkoxy.
10. The compound or salt of claim 4 , wherein:
X 1 and X 2 are independently a bond or methylene and X 1 is meta or para to the position of nitrogen attachment;
R is
R1 is Br, Cl, or —CF 3 ;
R4 is -x-y-z, wherein
x is C 4-6 cycloalkyl, phenyl, pyrazolyl, pyrrolidinyl, piperidinyl, or piperazinyl; y is absent, piperidinyl, or piperazinyl; and z is absent, C 1-3 alkyl optionally substituted by 1-2 hydroxy groups, or z is hydroxy or —C(O)O—C 0-3 alkyl; or
-x-y-z is C 0-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, or C 0-6 alkyl, each optionally substituted by 1-2 hydroxy;
R5 is methyl; and
R6 is H or methoxy.
11. The compound or salt of claim 10 , wherein R 9 and R 10 are independently C 0-3 alkoxy.
12. The compound or salt of claim 10 , wherein R4 is C 4-6 cycloalkyl which is optionally substituted by hydroxy, piperazinyl that is optionally N-methyl substituted, —C(O)O—C 0-3 alkyl, or C 1-3 alkyl optionally substituted by 1-2 hydroxy groups.
13. The compound or salt of claim 10 , wherein:
X 1 is a methylene group positioned meta to R6;
X 2 is a bond;
R1 is —CF 3 ; and
R4 is -x-y-z, wherein
x is C 4-6 cycloalkyl, phenyl, pyrazolyl, pyrrolidinyl, piperidinyl, or piperazinyl;
y is absent; and
z is absent, C 1-3 alkyl optionally substituted by 1-2 hydroxy groups, hydroxy, or —C(O)O—C 0-3 alkyl.
14. A compound selected from any one of Examples 1-329 herein or a pharmaceutically acceptable salt thereof.
15. The compound or salt of claim 4 , which is present as a material in substantially pure form.
16. The compound or salt of claim 4 , which exhibits inhibition of FAK in a MIA-PaCa2 or U87MG assay with an IC 50 of about 1 μM or less.
17. The compound or salt of claim 4 , which has an oral bioavailability (F) of at least about 30%.
18. The compound or salt of claim 4 , which exhibits an oral exposure AUC(0-∞) of at least about 2 μg h/mL with 20 mg/kg oral dosing in mouse.
19. A pharmaceutical composition comprising the compound or salt of claim 4 , formulated with or without one or more pharmaceutical carriers.
20. A method of treating a cancer mediated at least in part by FAK and selected from breast or ovarian cancer comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of claim 4 .
21. A compound or salt of claim 1 , which is: diethyl (3-methoxy-4-{[4-{[2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate.
22. A compound or salt of claim 1 , which is: diethyl (4-{[4-{[7-(trans-4-hydroxycyclohexyl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl) phosphonate hydrochloride.
23. A compound or salt of claim 1 , which is: diethyl (3-methoxy-4-{[4-({2-methyl-7-[trans-4-(4-methylpiperazin-1-yl)cyclohexyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate.
24. A compound or salt of claim 1 , which is: 2-{2-[3-(Dimethylphosphinoylmethyl)phenylamino]-5-trifluoromethylpyrimidin-4-ylamino}-N-methylbenzamide.
25. A compound or salt of claim 1 , which is: 2-{[2-{[4-(Dimethylphosphoryl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide.